JPH08503952A - 抗アレルギー性トリアゾロベンズアゼピン誘導体 - Google Patents
抗アレルギー性トリアゾロベンズアゼピン誘導体Info
- Publication number
- JPH08503952A JPH08503952A JP6513720A JP51372094A JPH08503952A JP H08503952 A JPH08503952 A JP H08503952A JP 6513720 A JP6513720 A JP 6513720A JP 51372094 A JP51372094 A JP 51372094A JP H08503952 A JPH08503952 A JP H08503952A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- alkyl
- compound
- substituted
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000003266 anti-allergic effect Effects 0.000 title abstract description 11
- QDEVEJYEXBFIJD-UHFFFAOYSA-N triazolo[4,5-i][1]benzazepine Chemical class C1=CC2=CC=CC=NC2=C2C1=NN=N2 QDEVEJYEXBFIJD-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 24
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 7
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract 3
- -1 cyano, hydroxy Chemical group 0.000 claims description 50
- 239000002253 acid Substances 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 20
- 239000002585 base Substances 0.000 claims description 15
- 150000002576 ketones Chemical class 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- VCZZOZNGVWEIIQ-UHFFFAOYSA-N 11-(1-methylpiperidin-4-ylidene)-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CCN2N=CN=C21 VCZZOZNGVWEIIQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 238000005810 carbonylation reaction Methods 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 241000255925 Diptera Species 0.000 claims 1
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- 239000012024 dehydrating agents Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 238000011426 transformation method Methods 0.000 claims 1
- JVCUBYFUMAWSBI-UHFFFAOYSA-N triazolo[4,5-b]azepine Chemical group N1=CC=CC=C2N=NN=C21 JVCUBYFUMAWSBI-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 106
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 65
- 239000000543 intermediate Substances 0.000 description 54
- 238000002844 melting Methods 0.000 description 45
- 230000008018 melting Effects 0.000 description 45
- 239000000243 solution Substances 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 239000003480 eluent Substances 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 7
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- YGLDQFWPUCURIP-UHFFFAOYSA-N 3h-3-benzazepine Chemical compound C1=CNC=CC2=CC=CC=C21 YGLDQFWPUCURIP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- DFSSQKKFQGHAEM-UHFFFAOYSA-N 3h-triazolo[5,1-b][3]benzazepine Chemical compound C1=CN2NN=CC2=CC2=CC=CC=C21 DFSSQKKFQGHAEM-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 150000001342 alkaline earth metals Chemical class 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- LKIYWJKEOOFVCV-UHFFFAOYSA-N 1-methylpiperidine-4-carbaldehyde Chemical compound CN1CCC(C=O)CC1 LKIYWJKEOOFVCV-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- IHCCAYCGZOLTEU-UHFFFAOYSA-N 3-furoic acid Chemical compound OC(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NZSOBBJIQGRKMO-UHFFFAOYSA-N OC(=O)C(O)=O.C1=CN2NN=CC2=CC2=CC=CC=C21 Chemical compound OC(=O)C(O)=O.C1=CN2NN=CC2=CC2=CC=CC=C21 NZSOBBJIQGRKMO-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229920002055 compound 48/80 Polymers 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- CUJPFPXNDSIBPG-UHFFFAOYSA-N 1,3-propanediyl Chemical group [CH2]C[CH2] CUJPFPXNDSIBPG-UHFFFAOYSA-N 0.000 description 1
- OMIVCRYZSXDGAB-UHFFFAOYSA-N 1,4-butanediyl Chemical group [CH2]CC[CH2] OMIVCRYZSXDGAB-UHFFFAOYSA-N 0.000 description 1
- OXHPTABOQVHKLN-UHFFFAOYSA-N 1-(2-bromoethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCBr)C=C1 OXHPTABOQVHKLN-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 1
- OQPAESNIQHSQAY-UHFFFAOYSA-N 11-(1-methylpiperidin-4-yl)-3-phenyl-5,6-dihydro-[1,2,4]triazolo[3,4-b][3]benzazepin-11-ol Chemical compound C1CN(C)CCC1C1(O)C2=CC=CC=C2CCN2C(C=3C=CC=CC=3)=NN=C21 OQPAESNIQHSQAY-UHFFFAOYSA-N 0.000 description 1
- FBVMKWFLOJZWGE-UHFFFAOYSA-N 11-(1-methylpiperidin-4-yl)-5,6-dihydro-[1,2,4]triazolo[3,4-b][3]benzazepin-11-ol Chemical compound C1CN(C)CCC1C1(O)C2=CC=CC=C2CCN2C=NN=C21 FBVMKWFLOJZWGE-UHFFFAOYSA-N 0.000 description 1
- OTWORBQMIXHTPR-UHFFFAOYSA-N 11-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[3,4-b][3]benzazepin-11-ol Chemical compound C1CN(C)CCC1C1(O)C2=CC=CC=C2C=CN2C=NN=C21 OTWORBQMIXHTPR-UHFFFAOYSA-N 0.000 description 1
- DGCIWOUWCURBDS-UHFFFAOYSA-N 11-[1-(2-ethoxyethyl)piperidin-4-ylidene]-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepine Chemical compound C1CN(CCOCC)CCC1=C1C2=CC=CC=C2CCN2N=CN=C21 DGCIWOUWCURBDS-UHFFFAOYSA-N 0.000 description 1
- MSQUWZNSXIHODJ-UHFFFAOYSA-N 11-[1-[2-(4-methoxyphenyl)ethyl]piperidin-4-ylidene]-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepine Chemical compound C1=CC(OC)=CC=C1CCN(CC1)CCC1=C1C2=CC=CC=C2CCN2N=CN=C21 MSQUWZNSXIHODJ-UHFFFAOYSA-N 0.000 description 1
- HNFVYSOTJKOXKV-UHFFFAOYSA-N 11h-[1,2,4]triazolo[3,4-b][3]benzazepine Chemical compound C1=CC2=CC=CC=C2CC2=NN=CN21 HNFVYSOTJKOXKV-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- MWNAZIHMWDUIRV-UHFFFAOYSA-N 2-(2-phenylethyl)-1,2,4-triazole-3-carbaldehyde Chemical compound O=CC1=NC=NN1CCC1=CC=CC=C1 MWNAZIHMWDUIRV-UHFFFAOYSA-N 0.000 description 1
- SCMLJWNXQGVQDX-UHFFFAOYSA-N 2-[4-(5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepin-11-ylidene)piperidin-1-yl]acetonitrile Chemical compound C1CN(CC#N)CCC1=C1C2=CC=CC=C2CCN2N=CN=C21 SCMLJWNXQGVQDX-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- NCDLFYLLYQXPCS-UHFFFAOYSA-N 2-chloro-1-methylpiperidine Chemical compound CN1CCCCC1Cl NCDLFYLLYQXPCS-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- NFPBWZOKGZKYRE-UHFFFAOYSA-N 2-propan-2-ylperoxypropane Chemical compound CC(C)OOC(C)C NFPBWZOKGZKYRE-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- DDKUANZENXTBIW-UHFFFAOYSA-N 3-[4-(8-fluoro-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepin-11-ylidene)piperidin-1-yl]propanoic acid;dihydrate Chemical compound O.O.C1CN(CCC(=O)O)CCC1=C1C2=CC=C(F)C=C2CCN2N=CN=C21 DDKUANZENXTBIW-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- WRSWLRMIQVHRCT-UHFFFAOYSA-N 3-methyl-6,11-dihydro-5h-[1,2,4]triazolo[4,3-c][3]benzazepine Chemical compound C1CN2C(C)=NN=C2CC2=CC=CC=C21 WRSWLRMIQVHRCT-UHFFFAOYSA-N 0.000 description 1
- CBVHMNOYHPUGLA-UHFFFAOYSA-N 3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-c][3]benzazepin-11-one Chemical compound N12CCC3=CC=CC=C3C(=O)C2=NN=C1C1=CC=CC=C1 CBVHMNOYHPUGLA-UHFFFAOYSA-N 0.000 description 1
- PWZNMPJNTVFLJR-UHFFFAOYSA-N 3-phenyl-6,11-dihydro-5h-[1,2,4]triazolo[4,3-c][3]benzazepine Chemical compound C1C2=CC=CC=C2CCN2C1=NN=C2C1=CC=CC=C1 PWZNMPJNTVFLJR-UHFFFAOYSA-N 0.000 description 1
- RSVUPJLESSWPGE-UHFFFAOYSA-N 3-pyridin-4-yl-5,6-dihydro-[1,2,4]triazolo[4,3-c][3]benzazepin-11-one Chemical compound N12CCC3=CC=CC=C3C(=O)C2=NN=C1C1=CC=NC=C1 RSVUPJLESSWPGE-UHFFFAOYSA-N 0.000 description 1
- TYWSTEOOYLFEJA-UHFFFAOYSA-N 3-pyridin-4-yl-6,11-dihydro-5h-[1,2,4]triazolo[4,3-c][3]benzazepine Chemical compound C1C2=CC=CC=C2CCN2C1=NN=C2C1=CC=NC=C1 TYWSTEOOYLFEJA-UHFFFAOYSA-N 0.000 description 1
- SCHRRVXSPNLRMS-UHFFFAOYSA-N 3h-pyrrolo[2,1-b][3]benzazepine Chemical class C1=CN2CC=CC2=CC2=CC=CC=C21 SCHRRVXSPNLRMS-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 1
- MYGXGCCFTPKWIH-UHFFFAOYSA-N 4-chloro-1-methylpiperidine Chemical compound CN1CCC(Cl)CC1 MYGXGCCFTPKWIH-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 description 1
- MIRJUCOWHKMBBU-UHFFFAOYSA-N 5,6-dihydro-[1,2,4]triazolo[4,3-c][3]benzazepin-11-one Chemical compound C1CC2=CC=CC=C2C(=O)C2=NN=CN21 MIRJUCOWHKMBBU-UHFFFAOYSA-N 0.000 description 1
- UXAXAHDXUWWYAL-UHFFFAOYSA-N 6,11-dihydro-5h-[1,2,4]triazolo[4,3-c][3]benzazepine Chemical compound C1CN2C=NN=C2CC2=CC=CC=C12 UXAXAHDXUWWYAL-UHFFFAOYSA-N 0.000 description 1
- QSPZNFNDTFEOAN-UHFFFAOYSA-N 7-methyl-11-(1-methylpiperidin-4-yl)-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepin-11-ol Chemical compound C1CN(C)CCC1C1(O)C2=CC=CC(C)=C2CCN2N=CN=C21 QSPZNFNDTFEOAN-UHFFFAOYSA-N 0.000 description 1
- ZFAWUAIGKRKZGE-UHFFFAOYSA-N 7-methyl-11-piperidin-4-ylidene-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepine Chemical compound CC1=CC=CC2=C1CCN1N=CN=C1C2=C1CCNCC1 ZFAWUAIGKRKZGE-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- GOQYWJGFEFVJBV-UHFFFAOYSA-N 8-fluoro-11-(1-methylpiperidin-4-yl)-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepin-11-ol Chemical compound C1CN(C)CCC1C1(O)C2=CC=C(F)C=C2CCN2N=CN=C21 GOQYWJGFEFVJBV-UHFFFAOYSA-N 0.000 description 1
- FKNLGGGQHSPSLJ-KQGICBIGSA-N 8-fluoro-11-[1-[(E)-3-phenylprop-2-enyl]piperidin-4-ylidene]-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepine oxalic acid Chemical compound OC(=O)C(O)=O.C=1C(F)=CC=C2C=1CCN1N=CN=C1C2=C(CC1)CCN1C\C=C\C1=CC=CC=C1 FKNLGGGQHSPSLJ-KQGICBIGSA-N 0.000 description 1
- MFWFHNQJCWXTIS-UHFFFAOYSA-N 8-fluoro-11-piperidin-4-ylidene-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepine Chemical compound C=1C(F)=CC=C2C=1CCN1N=CN=C1C2=C1CCNCC1 MFWFHNQJCWXTIS-UHFFFAOYSA-N 0.000 description 1
- HJYNABHOTLLVBP-UHFFFAOYSA-N 8-fluoro-5,6-dihydro-[1,2,4]triazolo[1,5-c][3]benzazepin-11-one Chemical compound C1CN2N=CN=C2C(=O)C2=CC=C(F)C=C12 HJYNABHOTLLVBP-UHFFFAOYSA-N 0.000 description 1
- QONZQAMMDIZDLZ-UHFFFAOYSA-N 8-fluoro-6,11-dihydro-5h-[1,2,4]triazolo[1,5-c][3]benzazepin-11-ol Chemical compound C1CC2=CC(F)=CC=C2C(O)C2=NC=NN21 QONZQAMMDIZDLZ-UHFFFAOYSA-N 0.000 description 1
- WSGBRGBXTUYQLL-UHFFFAOYSA-N 8-methoxy-11-(1-methylpiperidin-4-ylidene)-5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepine Chemical compound C=1C(OC)=CC=C2C=1CCN1N=CN=C1C2=C1CCN(C)CC1 WSGBRGBXTUYQLL-UHFFFAOYSA-N 0.000 description 1
- OYKWRNLXDYCSHQ-UHFFFAOYSA-N 9-chloro-5,6-dihydro-[1,2,4]triazolo[1,5-c][3]benzazepin-11-one Chemical compound C1CN2N=CN=C2C(=O)C2=CC(Cl)=CC=C21 OYKWRNLXDYCSHQ-UHFFFAOYSA-N 0.000 description 1
- LMGJONCHBMZSHZ-UHFFFAOYSA-N 9-chloro-6,11-dihydro-5H-[1,2,4]triazolo[1,5-c][3]benzazepin-11-ol Chemical compound ClC1=CC2=C(CCN3C(C2O)=NC=N3)C=C1 LMGJONCHBMZSHZ-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- IQTUDDBANZYMAR-WDSKDSINSA-N Asn-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(N)=O IQTUDDBANZYMAR-WDSKDSINSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- GHKIVXKYNADBHU-UHFFFAOYSA-N C1=CC2=C(C=CN3C(=C2)C=NN3)C(=C1)O Chemical compound C1=CC2=C(C=CN3C(=C2)C=NN3)C(=C1)O GHKIVXKYNADBHU-UHFFFAOYSA-N 0.000 description 1
- HVODDRKCLFQWKT-UHFFFAOYSA-N C1=CN(C=CC2=C1C=CC=C2)CO Chemical compound C1=CN(C=CC2=C1C=CC=C2)CO HVODDRKCLFQWKT-UHFFFAOYSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 241001072332 Monia Species 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 101000988638 Rattus norvegicus Humanin-like protein Proteins 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 235000002357 Ribes grossularia Nutrition 0.000 description 1
- 244000171263 Ribes grossularia Species 0.000 description 1
- 240000007651 Rubus glaucus Species 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 229910052776 Thorium Inorganic materials 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- CRCMUGODXVIADL-UHFFFAOYSA-N [1,2,4]triazolo[3,4-b][3]benzazepin-11-one Chemical compound C1=CC2=CC=CC=C2C(=O)C2=NN=CN21 CRCMUGODXVIADL-UHFFFAOYSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- FZIZEIAMIREUTN-UHFFFAOYSA-N azane;cerium(3+) Chemical compound N.[Ce+3] FZIZEIAMIREUTN-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- 229940075894 denatured ethanol Drugs 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- ZNVNOOOKLIXACE-UHFFFAOYSA-N ethyl 4-(5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepin-11-ylidene)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=CC=CC=C2CCN2N=CN=C21 ZNVNOOOKLIXACE-UHFFFAOYSA-N 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229910001511 metal iodide Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- QYVTZALYZGUYJA-UHFFFAOYSA-N n-[2-[4-(5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepin-11-ylidene)piperidin-1-yl]ethyl]furan-3-carboxamide Chemical compound C1CC(=C2C3=CC=CC=C3CCN3N=CN=C32)CCN1CCNC(=O)C=1C=COC=1 QYVTZALYZGUYJA-UHFFFAOYSA-N 0.000 description 1
- GCKASQFFAMDDQN-UHFFFAOYSA-N n-[2-[4-(5,6-dihydro-[1,2,4]triazolo[5,1-b][3]benzazepin-11-ylidene)piperidin-1-yl]ethyl]pyrimidin-2-amine Chemical compound C1CC(=C2C3=CC=CC=C3CCN3N=CN=C32)CCN1CCNC1=NC=CC=N1 GCKASQFFAMDDQN-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000003930 superacid Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000004546 suspension concentrate Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pulmonology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.式 [式中、 それぞれの点線は独立して任意の結合を示し; R1は水素、ハロ、C1-4アルキル、ヒドロキシ又はC1-4アルキルオキシを示し ; R2は水素、ハロ、C1-4アルキル、ヒドロキシ又はC1-4アルキルオキシを示し ; R3は水素、C1-4アルキル又はハロを示し; −B=D−は式 −C(R4)=N− (a−1);又は −N=C(R5)− (a−2) の2価の基であり; R4は水素、C1-4アルキル、ヒドロキシカルボニルもしくはC1-4アルキルオキ シカルボニルで置換されたエテニル、ヒドロキシカルボニルもしくはC1-4アル キルオキシカルボニルで置換されたC1-4アルキル、ヒドロキシC1-4アルキル、 ホルミル又はヒドロキシカルボニルを示し; R5は水素、C1-4アルキル、ヒドロキシカルボニルもしくはC1-4アルキルオキ シカルボニルで置換されたエテニル、ヒドロキシカルボニルも しくはC1-4アルキルオキシカルボニルで置換されたC1-4アルキル、ヒドロキシ C1-4アルキル、ホルミル、ヒドロキシカルボニル、フェニル又はピリジニルを 示し; Lは水素;C1-6アルキル;ヒドロキシ、C1-4アルキルオキシ、ヒドロキシカル ボニル、C1-4アルキルオキシカルボニル、C1-4アルキルオキシカルボニルC1- 4 アルキルオキシ、ヒドロキシカルボニルC1-4アルキルオキシ、C1-4アルキル アミノカルボニルアミノ、C1-4アルキルアミノチオカルボニルアミノ、アリー ル及びアリールオキシから成る群より選ばれる1つの置換基で置換されたC1-6 アルキル;ヒドロキシ及びアリールオキシの両方で置換されたC1-6アルキル; C3-6アルケニル;アリールで置換されたC3-6アルケニルを示し; ここで各アリールはフェニル又はハロ、シアノ、ヒドロキシ、C1-4アルキル、 C1-4アルキルオキシ又はアミノカルボニルで置換されたフェニルを示すか;あ るいは Lは式 −Alk−Y−Het1 (b−1)、 −Alk−NH−CO−Het2 (b−2)、もしくは −Alk−Het3 (b−3) の基を示し、ここで AlkはC1-4アルカンジイルを示し; YはO、S又はNHを示し; Het1、Het2及びHet3はそれぞれ、場合により1つ又は2つのC1-4アル キル置換基で置換されていることができるフラニル、チエニル、オキサゾリル、 チアゾリル又はイミダゾリル;場合によりホルミル、 ヒドロキシC1-4ァルキル、ヒドロキシカルボニル、C1-4アルキルオキシカルボ ニル又は1つもしくは2つのC1-4アルキル置換基で置換されていることができ るピロリル又はピラゾリル;場合によりアミノ又はC1-4アルキルで置換されて いることができるチアジアゾリル又はオキサジアゾリル;それぞれ場合によりC1-4 アルキル、C1-4アルキルオキシ、アミノ、ヒドロキシ又はハロにより置換さ れていることができるピリジニル、ピリミジニル、ピラジニル又はピリダジニル を示し; Het3はまたC1-4アルキルで置換された4,5−ジヒドロ−5−オキソ−1H −テトラゾリル、2−オキソ−3−オキサゾリジニル、2,3−ジヒドロ−2− の基を示すこともでき、ここで −A−Z−は−S−CH=CH−、−S−CH2−CH2−、−S−CH2−CH2 −CH2−、−CH=CH−CH=CH−又は−CH2−CH2−CH2−CH2− を示す] の化合物、それらの製薬学的に許容し得る付加塩及び立体化学的異性体。 2.−B=D−が式−C(R4)=N−(a−1)の2価の基である請求の範囲 第1項に記載の化合物。 3.LがC1-4アルキル又は式Alk−Het3(b−3)の基を示す請求の範囲 第2項に記載の化合物。 4.該化合物が6,11−ジヒドロ−11−(1−メチル−4−ピペリ ジニリデン)−5H−1,2,4−トリアゾロ[5,1−b][3]ベンズアゼ ピン、それらの立体化学的異性体又はそれらの酸付加塩である請求の範囲第1項 に記載の化合物。 5.活性成分として治療的有効量の請求の範囲第1項に記載の化合物及び製薬学 的に許容し得る担体を含む製薬学的組成物。 6.治療的有効量の請求の範囲第1項に記載の化合物を製薬学的担体と均質に混 合することを特徴とする請求の範囲第5項に記載の製薬学的組成物の製造法。 7.医薬品として用いるための請求の範囲第1項に記載の化合物。 8.式 [式中、 それそれの点線は独立して任意の結合を示し、 R1は水素、ハロ、C1-4アルキル、ヒドロキシ又はC1-4アルキルオキシを示し ; R2は水素、ハロ、C1-4アルキル、ヒドロキシ又はC1-4アルキルオキシを示し ; R3は水素、C1-4アルキル又はハロを示し; −B=D−は式 −C(R4)=N− (a−1);又は −N=C(R5)− (a−2) の2価の基であり; R4は水素、C1-4アルキル、ヒドロキシカルボニルもしくはC1-4アルキルオキ シカルボニルで置換されたエテニル、ヒドロキシカルボニルもしくはC1-4アル キルオキシカルボニルで置換されたC1-4アルキル、ヒドロキシC1-4アルキル、 ホルミル又はヒドロキシカルボニルを示し;R5は水素、C1-4アルキル、ヒドロ キシカルボニルもしくはC1-4アルキルオキシカルボニルで置換されたエテニル 、ヒドロキシカルボニルもしくはC1-4アルキルオキシカルボニルで置換された C1-4アルキル、ヒドロキシC1-4アルキル、ホルミル、ヒドロキシカルボニル、 フェニル又はピリジニルを示し; QはC1-6アルキルオキシカルボニル、C1-4アルキルカルボニル又はハロ、シア ノ、アミノもしくはメチルスルホニルオキシで置換されたC1-6アルキルを示す ] を有する化合物、それらの付加塩又はそれらの立体化学的異性体。 9.式 [式中、点線、R1、R2、R3及び−B=D−は請求の範囲第1項において定義 された通りであり、但し11H−1,2,4−トリアゾロ[3, 4−b][3]ベンズアゼピンを除く] を有する化合物及びそれらの付加塩の形態又はそれらの立体化学的異性体。 10.a)式(11)のアルコール又は式(III)のケトンを酸の存在中で環 化する; b)Wが適当な脱離基を示す式(IV)の中間体を反応に不活性な溶媒中で環化 し、かくして3環状部分の中心環が任意の結合を含まない式(I)の化合物を得 る; c)当該技術分野において既知の方法に従って式(V)又は(VI)のアルコー ルを脱水剤を用いて脱水し、ピペリジニル部分及びトリアゾロアゼピン部分の間 に二重結合が存在する式(I)の化合物を得る; d)当該技術分野おいて既知の方法に従って接触水素化することにより式(I− a)の化合物を式(I−b)の化合物に変換する e)塩基の存在中でC1-4アルキルクロロホルメートを用いて式(I−c)の化 合物を脱アルキル化−カルボニル化し、かくして得られる式(V II−a)の化合物を続いて当該技術分野において既知の方法に従って加水分解 し、かくしてLが水素である式(I)の化合物を得る; f)反応に不活性な溶媒中で式(I−c)の化合物とα−ハロ−C1-4アルキル クロロホルメートを反応させ、かくして式(I−d)の化合物を得る; g)水素及び適当な触媒の存在中で式(I−e)の化合物を接触水素化し、かく して式(I−d)の化合物を得る; h)反応に不活性な溶媒中で、場合により塩基の存在中において式L1−W(V III)の試薬を用いて式(I−d)の化合物をN−アルキル化し、かくしてL が水素以外であり、該LがL1により示される式(I)の化合物を得る; i)当該技術分野において既知の方法に従って式(I−d)の化合物を還元的にN −アルキル化し、かくしてLがC1-6アルキル又は置換C1-6アルキルである式 (I)の化合物を得る; j)当該技術分野において既知の方法に従って式(I−d)の化合物をアルケン と反応させ、かくしてLがC1-6アルキル又は置換C1-6アルキルである式(I) の化合物を得る; k)当該技術分野において既知の方法に従って式(I−d)の化合物をエポキシ ドと反応させ、かくしてLがヒドロキシで置換されたC1-6アルキルである式( I)の化合物を得る; l)R4又はR5が水素である式(I)の化合物を酸の存在中でアルデヒドと反応 させ、かくしてR4又はR5がヒドロキシC1-4アルキルである式(I)の化合物 を得る; そして必要ならばさらに、当該技術分野において既知の官能基変換法に従って式 (I)の化合物を互いに変換し;式(I)の化合物を製薬学的に許容し得る酸又 は塩基で処理することにより塩の形態に変換し;あるいは逆にそれぞれアルカリ 又は酸で処理することにより塩の形態を遊離の塩基又は遊離の酸に変換し;及び /又はそれらの立体化学的異性体を製造する ことを特徴とする請求の範囲第1項に記載の化合物の製造法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP92203776 | 1992-12-04 | ||
EP92203776.7 | 1992-12-04 | ||
PCT/EP1993/003320 WO1994013671A1 (en) | 1992-12-04 | 1993-11-25 | Antiallergic triazolobenzazepine derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH08503952A true JPH08503952A (ja) | 1996-04-30 |
JP3572074B2 JP3572074B2 (ja) | 2004-09-29 |
Family
ID=8211104
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51372094A Expired - Fee Related JP3572074B2 (ja) | 1992-12-04 | 1993-11-25 | 抗アレルギー性トリアゾロベンズアゼピン誘導体 |
Country Status (16)
Country | Link |
---|---|
US (1) | US5932569A (ja) |
EP (1) | EP0675887B1 (ja) |
JP (1) | JP3572074B2 (ja) |
KR (1) | KR100251893B1 (ja) |
AT (1) | ATE236164T1 (ja) |
AU (1) | AU676701B2 (ja) |
CA (1) | CA2150806C (ja) |
DE (1) | DE69332830T2 (ja) |
ES (1) | ES2196020T3 (ja) |
FI (1) | FI952722A0 (ja) |
HU (1) | HU223464B1 (ja) |
NO (1) | NO305250B1 (ja) |
NZ (1) | NZ258551A (ja) |
PL (1) | PL176593B1 (ja) |
RU (1) | RU2126802C1 (ja) |
WO (1) | WO1994013671A1 (ja) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3503065B2 (ja) * | 1992-12-04 | 2004-03-02 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノート シヤツプ | 抗アレルギー性トリアゾロ(ピロロ、チエノ又はフラノ)アゼピン誘導体 |
CA2448735C (en) | 2001-06-12 | 2008-10-28 | Janssen Pharmaceutica N.V. | Novel substituted tetracyclic imidazole derivatives, processes for their preparation, pharmaceutical compositions comprising them and their use as a medicine |
EP1785424A3 (en) * | 2003-04-11 | 2009-12-23 | High Point Pharmaceuticals, LLC | Fused 1,2,4-triazoles and pharmaceutical uses thereof |
DK1615647T3 (da) * | 2003-04-11 | 2010-04-06 | High Point Pharmaceuticals Llc | Farmaceutisk anvendelse af kondenserede 1,2,4-triazoler |
WO2006040329A1 (en) * | 2004-10-12 | 2006-04-20 | Novo Nordisk A/S | 1 ibeta- hydroxysteroid dehydrogenase type 1 active spiro compounds |
JP2009514818A (ja) * | 2005-11-01 | 2009-04-09 | ハイ ポイント ファーマシューティカルズ,リミティド ライアビリティ カンパニー | 置換アミドの製薬学的用途 |
EP1945207A2 (en) * | 2005-11-01 | 2008-07-23 | Transtech Pharma, Inc. | Pharmaceutical use of substituted amides |
WO2007107550A1 (en) * | 2006-03-21 | 2007-09-27 | High Point Pharmaceuticals, Llc | Adamantane derivatives for the treatment of the metabolic syndrome |
BRPI0710669A2 (pt) | 2006-04-07 | 2011-08-16 | High Point Pharmaceuticals Llc | compostos ativos de dehidrogenase de 11b-hidroxiesteróide tipo 1 |
US8048908B2 (en) * | 2006-07-13 | 2011-11-01 | High Point Pharmaceuticals, Llc | 11β-hydroxysteroid dehydrogenase type 1 active compounds |
EP1878721A1 (en) * | 2006-07-13 | 2008-01-16 | Novo Nordisk A/S | 4-Piperidylbenzamides as 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors |
US8334305B2 (en) * | 2007-02-23 | 2012-12-18 | High Point Pharmaceuticals, Llc | N-adamantyl benzamides as inhibitors of 11-β-hydroxysteroid dehydrogenase |
US20110003852A1 (en) * | 2007-02-23 | 2011-01-06 | Soren Ebdrup | N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase |
JP2010519240A (ja) * | 2007-02-23 | 2010-06-03 | ハイ ポイント ファーマシューティカルズ,リミティド ライアビリティ カンパニー | 11−ベータ−ヒドロキシステロイドデヒドロゲナーゼの阻害剤としての、n−アダマンチルベンズアミド |
BRPI0806847A2 (pt) | 2007-02-23 | 2014-04-29 | High Point Pharmaceuticals Llc | N-adamantil benzamidas como inibidores de 11-beta-hidroxiesteróide desidrogenase |
EP2134705A1 (en) * | 2007-03-09 | 2009-12-23 | High Point Pharmaceuticals, LLC | Indole- and benzimidazole amides as hydroxysteroid dehydrogenase inhibitors |
JP2010522766A (ja) * | 2007-03-28 | 2010-07-08 | ハイ ポイント ファーマシューティカルズ,リミティド ライアビリティ カンパニー | 11ベータ−hsd1活性化合物 |
WO2008127924A1 (en) * | 2007-04-11 | 2008-10-23 | High Point Pharmaceuticals, Llc. | Novel compounds |
ES2393230T3 (es) * | 2007-04-24 | 2012-12-19 | High Point Pharmaceuticals, Llc | Uso farmacéutico de amidas sustituidas |
DK3186242T3 (da) | 2014-08-29 | 2021-12-20 | Tes Pharma S R L | Alfa-amino-beta-carboxymuconsyre-semialdehyd-decarboxylasehæmmere |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU8902591A (en) * | 1990-10-10 | 1992-05-20 | Schering Corporation | Substituted imidazobenzazepines and imidazopyridoazepines |
IL101850A (en) * | 1991-06-13 | 1996-01-31 | Janssen Pharmaceutica Nv | History 11-) 4-Pipridinyl (-Imidazo] B-1, 2 [] 3 [Benzazepine, their preparation and pharmaceutical preparations containing them |
JP3503065B2 (ja) * | 1992-12-04 | 2004-03-02 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノート シヤツプ | 抗アレルギー性トリアゾロ(ピロロ、チエノ又はフラノ)アゼピン誘導体 |
DE69332929T2 (de) * | 1992-12-04 | 2004-02-26 | Janssen Pharmaceutica N.V. | ANTIALLERGISCHE IMIDAZO[1,2-a]THIENO[2,3-d]AZEPINDERIVATE |
-
1993
- 1993-11-25 US US08/433,388 patent/US5932569A/en not_active Expired - Fee Related
- 1993-11-25 AT AT94901886T patent/ATE236164T1/de not_active IP Right Cessation
- 1993-11-25 ES ES94901886T patent/ES2196020T3/es not_active Expired - Lifetime
- 1993-11-25 JP JP51372094A patent/JP3572074B2/ja not_active Expired - Fee Related
- 1993-11-25 NZ NZ258551A patent/NZ258551A/en unknown
- 1993-11-25 EP EP94901886A patent/EP0675887B1/en not_active Expired - Lifetime
- 1993-11-25 RU RU95114439A patent/RU2126802C1/ru not_active IP Right Cessation
- 1993-11-25 HU HU9501621A patent/HU223464B1/hu not_active IP Right Cessation
- 1993-11-25 WO PCT/EP1993/003320 patent/WO1994013671A1/en active IP Right Grant
- 1993-11-25 AU AU56278/94A patent/AU676701B2/en not_active Ceased
- 1993-11-25 PL PL93309253A patent/PL176593B1/pl not_active IP Right Cessation
- 1993-11-25 KR KR1019950702169A patent/KR100251893B1/ko not_active IP Right Cessation
- 1993-11-25 DE DE69332830T patent/DE69332830T2/de not_active Expired - Fee Related
- 1993-11-25 CA CA002150806A patent/CA2150806C/en not_active Expired - Fee Related
-
1995
- 1995-06-02 NO NO952198A patent/NO305250B1/no unknown
- 1995-06-02 FI FI952722A patent/FI952722A0/fi unknown
Also Published As
Publication number | Publication date |
---|---|
ATE236164T1 (de) | 2003-04-15 |
NO952198L (no) | 1995-08-03 |
PL309253A1 (en) | 1995-10-02 |
KR100251893B1 (ko) | 2000-04-15 |
EP0675887B1 (en) | 2003-04-02 |
DE69332830D1 (de) | 2003-05-08 |
FI952722A (fi) | 1995-06-02 |
NO305250B1 (no) | 1999-04-26 |
AU676701B2 (en) | 1997-03-20 |
NO952198D0 (no) | 1995-06-02 |
HUT71811A (en) | 1996-02-28 |
NZ258551A (en) | 1996-06-25 |
AU5627894A (en) | 1994-07-04 |
JP3572074B2 (ja) | 2004-09-29 |
HU223464B1 (hu) | 2004-07-28 |
ES2196020T3 (es) | 2003-12-16 |
DE69332830T2 (de) | 2004-01-29 |
CA2150806C (en) | 2006-01-31 |
CA2150806A1 (en) | 1994-06-23 |
RU95114439A (ru) | 1997-06-10 |
EP0675887A1 (en) | 1995-10-11 |
HU9501621D0 (en) | 1995-08-28 |
RU2126802C1 (ru) | 1999-02-27 |
PL176593B1 (pl) | 1999-06-30 |
FI952722A0 (fi) | 1995-06-02 |
WO1994013671A1 (en) | 1994-06-23 |
US5932569A (en) | 1999-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH08503952A (ja) | 抗アレルギー性トリアゾロベンズアゼピン誘導体 | |
JP2845407B2 (ja) | イミダゾ[2,1−b][3]ベンズアゼピン誘導体、組成物及び利用法 | |
EP0730594B1 (en) | 9-HYDROXY-PYRIDO [1,2-a]PYRIMIDIN-4-ONE ETHER DERIVATIVES | |
JPH06507890A (ja) | イミダゾ[1,2−a](ピロロ、チエノ又はフラノ)[3,2−d]アゼピン誘導体、組成物及び利用法 | |
KR850000413B1 (ko) | 3-(1-피페리디닐알킬)-4H-피리도[1, 2-a]피리미딘-4-온 유도체의 제조방법 | |
JP3503064B2 (ja) | 抗アレルギー性イミダゾ[1,2,−a](ピロロ、チエノ又はフラノ)[2,3−d]アゼピン誘導体 | |
JP3681388B2 (ja) | 抗アレルギー性イミダゾアゼピン | |
JP3503065B2 (ja) | 抗アレルギー性トリアゾロ(ピロロ、チエノ又はフラノ)アゼピン誘導体 | |
JPH0480913B2 (ja) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20040216 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20040520 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20040601 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20040628 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20070702 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20080702 Year of fee payment: 4 |
|
LAPS | Cancellation because of no payment of annual fees |